Estrogens affect a wide variety of processes in the brain and many aspects of behavior including social interactions, reproduction, and memory. A variety of estrogen receptors (ER) and signaling pathways make up a complex regulatory network that produces intriguing examples of functional plasticity. For example, at ovulation estrogens switch from exerting negative feedback on gonadotropin releasing hormone to exerting positive feedback. Negative feedback is mediated in part by rapid acting nongenomic effects of estrogens whereas positive feedback relies on a sustained increase in estrogens that apparently drives changes in gene expression. Recent studies on Peromyscus identified a similar pattern for male behavior. Estrogens decrease aggressive behavior in mice housed in long days (16L:8D) but increase aggressive behavior in mice housed in short days (8L:16D). This functional plasticity appears to be mediated by a fundamental change in the down-stream effects of ERs. In long days, hormone manipulations affect behavior only after 10 days. Microarray analyses showed increased estrogen-regulated transcription in the brain under long days compared to short days. This suggests that estrogens may decrease aggression by driving transcription. In short day's estradiol injections increase aggression within 15 minutes, suggesting these effects are mediated by nongenomic pathways. This proposal, submitted by a new investigator, examines how a photoperiod modulates the effects of estrogens on aggression. Using behavioral, cellular, and molecular analyses of aggressive behavior we outline how the different environments can induce functional plasticity in estrogen regulated behavior. Dysregulated aggression is a component of mental disorders including bipolar disorder, schizophrenia, and borderline personality disorder. Correlational and clinical trial data suggest that estrogens affect aggressive behavior in men and women. However, virtually all studies examining the effects of estrogens on human behavior utilize either peripheral hormone manipulations or measurements. There is growing appreciation that steroid hormones are synthesized de novo in brain regions such as the hypothalamus and hippocampus. Recent data show estrogen synthesis in the brain is modulated by social interactions on a moment-to- moment basis. This strongly suggests that rapid actions of estrogens synthesized in the brain may be of critical important for behavior. These observations require us to reassess how we view the relationships between estrogens and behavior in humans, because the vast majority of human studies only consider estrogens derived from gonadal hormones. In our studies we can investigate both slow (genomic) and rapid (nongenomic) mechanisms of aggression simply by manipulating photoperiod, giving us a unique opportunity to examine how estrogens interact with the environment to affect behavior. We hypothesize that the differential effects of estrogens on aggression are mediated by differences in genomic and nongenomic activation. In the first specific aim we will confirm whether estrogens increase aggression by acting nongenomically. In the second specific aim we will use immunohistochemistry and western blots to identify intracellular signaling pathways that could mediate the rapid effects of estrogens on aggression. Finally we will use hormone manipulations and real-time PCR to test whether melatonin inhibits estrogen-dependent gene expression in the brain, thereby blocking genomic action in short-day mice. The proposed research will identify intracellular signaling pathways involved in regulating aggression and should provide insights for developing new strategies for managing exaggerated aggressive behaviors. PUBLIC HEALTH RELEVANCE: Estrogens affect a wide variety of processes in the brain and many aspects of behavior including social interactions, reproduction, and memory. The amount of light a male California mouse is exposed to each day determines whether estrogens increase or decrease aggression. The proposed research will investigate the cellular mechanisms that underlie this gene-environment interaction that affects a behavior associated with many mental disorders.